The current proposal seeks to continue mechanistic studies to understand, at the molecular level, the enzyme activities of RT and interaction of nucleoside inhibitors and the resistance of these compounds which develop through mutations. To achieve these aims, the investigator proposes (1) studies of the process of tRNA3lys initiation of HIV RT using an RNA duplex substrate. Because the tRNA will most likely have substantial secondary structures, the functional properties of this RNA duplex interaction with HIV RT may be different than the DNA duplex or RNA/DNA heteroduplex substrates previously used. (2) The relevance of the nucleocapsid protein as it is involved in both the rRNA3lys initiation and elongation processes and its role in the development of mutant RT. (3) Mechanistic studies will be conducted on the inhibition of mitochondrial gamma polymerase by nucleoside analogues which may be important to understand cytotoxicity.